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Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model  Sylvie Amu, PhD, Sean P.

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Presentation on theme: "Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model  Sylvie Amu, PhD, Sean P."— Presentation transcript:

1 Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model  Sylvie Amu, PhD, Sean P. Saunders, BSc, Mitchell Kronenberg, PhD, Niamh E. Mangan, PhD, Ann Atzberger, MSc, Padraic G. Fallon, PhD  Journal of Allergy and Clinical Immunology  Volume 125, Issue 5, Pages e8 (May 2010) DOI: /j.jaci Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Administration of B cells isolated from S mansoni–infected mice prevents the development of acute allergic airway inflammation. A, Representative hematoxylin and eosin–stained lung sections of ovalbumin (OVA)–sensitized mice. B, Methacholine-induced lung resistance (RL) in PBS-sensitized or OVA-sensitized mice. Total cells (C) and eosinophil counts (D) in the BAL. E, Methacholine-induced RL in PBS-sensitized or OVA-sensitized uninfected mice from groups as shown. Mice were treated with OVA in an acute sensitization model (Fig E1, A). Data represent the mean change from baseline values for each group. The Student t test was used to test for statistical difference between groups: ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Characterization of IL-10–producing Breg cells. A, Representative histograms of spleen IL-10+ cells from infected (black histogram) and uninfected (gray histogram) IL-10–eGFP mice that express CD19. CD1d expression on CD19+ or CD19+IL-10+ spleen cells in infected IL-10–eGFP mice, and isotype control. B, CD5, CD21, CD23, IgD, and IgM expression on CD19+IL-10+CD1dhigh Breg cells. Surface expression of markers on whole CD19+ cells and isotype control is shown. C, Numbers of Breg cells in the spleen of uninfected and infected mice. Data are from analysis of cells from individual mice and representative of 6 to 8 experiments. The Student t test was used to test for statistical difference between groups: ∗∗∗P < Max, Maximum. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 S mansoni–infected CD1d-/- mice are susceptible to acute allergic airway inflammation. A, Methacholine-induced lung resistance (RL) in ovalbumin (OVA)-sensitized uninfected and infected CD1d-/- or wild-type (WT) mice. Total cells (B) and eosinophils (C) in BAL. Mice were treated with OVA in an acute sensitization model (Fig E1, A). The Student t test was used to test for statistical difference between groups: ∗P < .05; ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Administration of in vivo–generated Breg cells prevents the development of acute allergic airway inflammation. A, Hematoxylin and eosin–stained lung sections from ovalbumin (OVA)–sensitized mice that were transferred Breg cells or CD1dlow B cells from infected mice. B, Methacholine-induced lung resistance (RL) in OVA-sensitized mice receiving in vivo–generated Breg or CD1dlow B cells, or no cells. C, Periodic acid-Schiff–stained lung sections from the OVA-sensitized mice receiving Breg or CD1dlow B cells. D, Mucus score for goblet cell hyperplasia. Total cells (E) and eosinophils (F) in BAL. G, BAL fluid cytokine levels in mice OVA-sensitized receiving no cells, Breg, or CD1dlow B cells. Mice were treated with OVA and Breg cells transferred in an acute sensitization model (Fig E1, A). The Mann-Whitney test was used for analysis of mucus score and the Student t test for BAL analysis. ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Administration of Breg cells expands pulmonary Treg cells. In vivo–generated Breg or CD1dlow B cells were transferred to ovalbumin-sensitized FoxP3-eGFP reporter mice, and the number of Treg cells (CD4+CD25+FoxP3+) was measured in lung digests (A), mediastinal lymph nodes (Med LN)(B), BAL (C), and spleen (D). E, Number of Treg cells in BAL of FoxP3-eGFP reporter mice OVA-sensitized receiving no cells, in vivo–generated Breg cells from wild-type mice, or CD1dhigh B cells from IL-10-/-–infected mice. Mice were treated with ovalbumin and cells transferred in an acute sensitization model (Fig E1, A). The Student t test was used to test for statistical difference between groups: ∗P < .05; ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Administration of in vivo–generated Breg cells prevents the development of acute allergic airway inflammation via a Treg-dependent and TGF-β–independent mechanism. A, Number of Treg cells in BAL from ovalbumin (OVA)–sensitized FoxP3-eGFP reporter mice receiving no cells, Breg cells, or Breg cells and anti–TGF-β or anti–IL-10-receptor(R) mAb. B, Treg-cell numbers in the lung digests from OVA-sensitized wild-type (WT) and CD4-dnTGFβRII mice after receiving no cells or Breg cells. C, Methacholine-induced lung resistance (RL) in OVA-sensitized uninfected mice, that were transferred Breg cells and treated with anti-CD25 or control mAb. Control mice not receiving Breg cells and untreated (OVA-alone) or treated with anti-CD25 mAb are shown. Mice were treated with OVA and Breg cells transferred in an acute sensitization model (Fig E1, A). Data represent the means ± SDs. The Student t test was used to test for groups with statistical difference from OVA-alone–treated mice: ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 Administration of in vivo–generated Breg cells reverses established allergic airway inflammation. A, Lung resistance (RL), in response to methacholine, of mice with established airway inflammation receiving in vivo–generated Breg cells. Total cells (B) and eosinophil cells (C) in BAL. D, Number of Treg cells in BAL. Data represent the means ± SDs. Mice were treated with ovalbumin (OVA) and Breg cells transferred in a model of established airway inflammation (Fig E1, B). The Student t test was used to test for statistical difference between groups: ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Ovalbumin(OVA) sensitization protocol for acute and established airway inflammation. A, Acute sensitization model: mice were sensitized with 20 μg OVA in alum i.p. on days 0 and 14. Airway challenge with 1% OVA was performed on days 21 to 24, concurrent with transfer of Breg cells. Lung analysis was performed on day 25. B, Established model: mice were sensitized with 20 μg OVA in alum i.p. on days 0 and 12. Mice received airway challenge with 5% OVA on days 16 to 19 and days 25 to 28. On days 36 to 39, mice received Breg cells and 5% OVA aerosol. On day 44, mice received 5 % OVA aerosol challenge. Lung analysis was performed on day 45. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Characterization of different B-cell subpopulations in spleens of uninfected and worm-infected mice. Representative flow-cytometry plots for uninfected and infected mice and the absolute numbers for each subpopulation are shown: B cells (CD19+), B1 B cells (CD19+IgM+CD43+IgD–), B2 B cells (CD19+IgMlowIgD+CD43–), B1a B cells (CD19+CD5+), T1 B cells (CD19+IgD–CD62L–CD21–CD23–), T2 B cells (CD19+IgD+CD62L+CD21+CD23+), MZ B cells (CD19+CD21+CD23–), follicular zone B cells (FO B cells; CD19+CD21–CD23+), CD1dhigh B cells (CD19+CD1dhigh), and plasma cells (CD19–CD138+). Cell populations are gated on live cells first and then on CD19+ B cells with 20,000 cells shown. Plasma cells are gated on live cells and then CD19– cells. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Role for CD1d in S mansoni–mediated protection against allergic airway inflammation and anaphylaxis. A, Lung resistance (RL) in response to methacholine of ovalbumin (OVA)–sensitized uninfected mice, and infected mice treated with an anti-CD1d mAb or a control mAb. Data represent the mean ± SEM change from baseline values for each group. B, Drop in temperature in Pen V–sensitized uninfected mice and infected mice treated with an anti-CD1d mAb or a control mAb. Anaphylaxis was induced by i.v. injection of Pen V. Data are mean ± SEM change in temperature. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 S mansoni–infected mice are refractory to allergic airway inflammation independent of iNKT cells. Flow-cytometry plots and absolute numbers of iNKT cells, identified by staining with mCD1d-PBS056 loaded tetramer and anti-TCRβ mAb, in spleens (A) and lungs (B) of uninfected and infected wild type (WT) and CD1d-/- mice that were sensitized to ovalbumin (OVA) or PBS. C, Lung resistance (RL) in response to methacholine of OVA-sensitized uninfected and infected WT and Jα18-/- mice. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Expansion of a CD1d– B-cell population that exacerbates allergic airway inflammation in the spleens of worm-infected mice. A, Representative flow-cytometry images of increased CD1d– B cells in spleen cells from infected mice compared to uninfected mice. B, Flow-cytometry histograms showing gated CD1d–CD19+ B cells from infected mice compared with the whole CD19+ population from uninfected mice and isotype control for expression of CD23, CD21, CD5, IgD, and IgM. C, Lung resistance (RL) in response to methacholine of ovalbumin (OVA)–sensitized uninfected mice transferred Breg cells or CD1d– B cells sorted from the spleens of infected mice. Recipients of CD1d– B cells died from 30 to 60 mg/mL methacholine exposure. Total cell (D) and eosinophil (E) counts in BAL from mice treated as described. Data are the means ± SEMs. The Student t test was used to test for statistical difference between groups as indicated: ∗∗P < .01; ∗∗∗P < Max, Maximum. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

14 Breg cells generated ex vivo by worms mediate protection against allergic airway inflammation and induce Treg cells in vivo. Spleen cells from uninfected mice were cultured for 48 hours with 5 worms or in medium. A, Spleen cells from IL-10–eGFP mice cultured in media or with worms for flow cytometry. After culture, the IL-10+–eGFP spleen cells were gated and the numbers of CD19+ B cells plotted. CD19+IL-10+ B cells from worm cultures (blue histogram) or media (red histogram) are shown. CD19+IL-10+ cells induced by worms express CD1d (blue histogram); isotype controls (black histogram). B, Representative hematoxylin and eosin–stained sections of lungs from ovalbumin (OVA)–sensitized mice that received ex vivo generated Breg cells. C, Lung resistance (RL) in response to methacholine of OVA-primed mice receiving ex vivo generated Breg cells. Untreated mice (PBS-Alone) or OVA-sensitized mice (OVA-Alone) were used as controls. D, Total number of Treg cells (CD4+CD25+Foxp3+) detected in BAL of mice sensitized with OVA and receiving no cells, Breg cells from medium cultures, and ex vivo worm–generated Breg cells. The Student t test was used to test for statistical difference between groups as indicated: ∗∗P < .01. Journal of Allergy and Clinical Immunology  , e8DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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